Parkinson's disease (PD) is a degenerative disorder of the central nervous system. Most cases are sporadic, although a subset of cases has a genetic origin. Increasing evidence points to a role of mitochondrial dysfunction in many forms of Parkinsonism.
Indeed, mitochondrial toxins, such as MPTP (1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine) and rotenone, but also various defects in the electron transport chain (ETC) are associated with sporadic PD6,7.
Mutations in PINK1, a mitochondrial targeted Ser/Thr kinase, cause a monogenic form of PD1,2. These human mutations, as well as absence of PINK1 in diverse animal models, are associated with ETC deficiencies3,5,8, supporting the hypothesis that defects in ETC are a major culprit in the pathogenesis of PD. However, no mechanisms have been proposed, and the alternative, not necessarily contradictory, hypothesis that mutations in PINK1 cause PD by interfering with the PARKIN-mediated CCCP-induced mitophagy pathway (clearance of defective mitochondria) has gained ground considerably9-11. Defects in mitochondrial clearance are linked to mitochondrial fusion/fission defects10, which could explain thorax muscle degeneration and flight deficits observed in pink1 and parkin Drosophila models12-14. These defects are indeed rescued by expression of the fission promoting gene Drp1 or ablating the fusion promoting gene Opal, respectively15,16. Intriguingly, other pink1-related phenotypes, such as defective neurotransmitter release and loss of mitochondrial membrane potential (Δψm) in Drosophila neurons, cannot be rescued by fission gene Drp117, but by genes restoring the proton motive force18, or by NDi1, a rotenone-insensitive NADH-quinone oxidoreductase of Saccharomyces cerevisiae17. These results confirm that two parallel pathways are affected in pink1B9 null Drosophila, one involved in clearance of defective mitochondria and another in the maintenance of Δψm. Each pathway might explain a different subset of phenotypes in the fly. In contrast, Pink1−/− mice display very subtle, and somewhat controversial, phenotypes of altered mitochondrial morphology in resting state3,8,19,20, and it is unclear to what extent decreased mitophagy or Complex I deficiency contributes to these defects.
It would be advantageous to identify defects underlying the mitochondrial deficiencies observed in PD. Particularly useful would be if these defects not only can help in diagnosing PD, but also point the way to new therapeutic paradigms.